An important neuropathological manifestation of Alzheimer's disease is the presence of amyloid depositions in brains and leptomeninges of afflicted individuals. However, amyloid depositions are not unique to Alzheimer's disease. They also occur in Down syndrome and hereditary cerebral hemorrhage with amyloidosis of the Dutch type and to a lesser degree in the normal aging brain. A major component of the amyloid plaque is the amyloid f3-protein (AB). This peptide is derived from a larger protein termed the amyloid precursor protein (APP) through proteolytic processing. Several lines of genetic evidence indicate that the pathological manifestations of Alzheimer's disease are a direct consequence of the deposition of AB. In addition, increased or altered APP expression, such as in Down syndrome, may be an important factor in a multistep process leading to the formation of amyloid deposits. This suggests that the progression of the disease might be delayed or arrested by reducing or eliminating APP expression and it emphasizes the importance of elucidating the mechanism of APP gene regulation. A sequence element in the proximal promoter region was found to be essential for high levels of expression. This element binds the multivalent and multifunctional transcription factor CTCF, which acts as a transcriptional activator. The precise region within the CTCF protein that mediates transcriptional activation will be identified by deletion and mutation analysis. The co-activator(s) that interacts with CTCF will be identified. In addition, further essential factors that encompass the transcription complex of the APP promoter will be identified. These include the components of the transcriptional initiation complex and other as yet uncharacterized APP promoter binding factors. Finally, the nucleosomal organization of the APP promoter will be examined for a better understanding of APP gene regulation in vivo. One ultimate goal of this research is to control APP gene expression in vivo by altering the interaction of activating factors with the APP promoter.